The neurodegenerative disease amyotrophic lateral sclerosis (ALS) can be caused by mutations in components of the intracellular motor protein dynein [1]. What, then, are the critical molecules transported by dyneins that are essential for neuronal survival? My colleagues and I have shown that dynein-based transport is required for survival of neurons that depend on target-derived neurotrophic factors. We have shown that this reflects the role of axonal dynein in mediating transport of activated neurotrophin receptors (Trks) within large signaling endosomes. Therefore, we hypothesize that ALS may result from deficiencies in long-range neurotrophic factor signaling, and that restoring these retrograde signals will provide an effective therapeutic approach to the disease. We have identified a set of genes that are preferentially induced by neurotrophin stimulation of distal axons (retrograde signals) rather than by stimulation of cell bodies . (anterograde signals), a set that we designate as retrograde response genes. The retrograde response gene set contains several members that are likely to protect cells from progressive neurodegeneration, including the anti-apoptotic gene bclw and the survival-promoting factor IGF-1. In the proposed studies we will build on our identification of spatially selective neurotrophin responses to determine the mechanisms and functions of specialized retrograde signals. We have three aims. 1. To determine the mechanisms responsible for induction of retrograde response genes by target-derived , neurotrophins, using both motor and sensory neurons grown in compartmented cultures. 2. To determine the functions of retrograde response genes in developing and mature neurons. We will focus on bclw, a poorly understood pro-survival bc!2 family member that is preferentially expressed in the mature nervous system, and can protect diverse neurons from apoptotic stimuli. 3. To test the hypothesis that mutations in dynein that cause ALS do so by interfering with the signaling pathways that induce bclw and other retrograde response genes. We will determine whether expression of these genes protects motor neurons from progressive degeneration. Understanding the mechanism and significance of long distance survival pathways may lead to new therapeutic approaches for ALS and other devastating neurodegenerative disorders.